BK virus nephropathy in a patient with ABO-incompatible renal transplantation

Abstract:  A 43-year-old woman with end-stage renal disease originating from IgA nephropathy entered chronic haemodialysis therapy. She then received an ABO-incompatible living related renal transplantation. Initial immunosuppression consisted of azathioprine, methylprednisolone and tacrolimus. At 155 days after transplantation, the azathioprine was changed to mycophenolate mofetil for continuous graft dysfunction. Furthermore, a total of three courses of anti-rejection therapy was given. At 665 days after transplantation, diagnosis of BK-virus nephropathy was made by immunohistochemical analysis and viral DNA assay. Therefore the immunosuppression therapy was reduced for graft dysfunction. All five renal biopsy specimens were examined retrospectively in order to determine when the BK virus nephropathy had developed. The expressions of SV40 large T antigens were detected from the third (117 days) to the fifth (665 days) biopsies, with increasing numbers of SV40 large T antigen positive cells. In addition, many cells contained inclusion bodies which were already present in the urinary sediment for 3 months post-transplantation. Although it is difficult to make a diagnosis of early stage of BKVN, we have to consider with caution if urinary cells with inclusion body are seen. Awareness of BKVN at the earliest opportunity is important in order to avoid over-immunosuppression.     

Comparison of alemtuzumab vs. antithymocyte globulin induction therapy in primary non‐sensitized renal transplant patients treated with rapid steroid withdrawal

Alemtuzumab and rabbit antithymocyte globulin (rATG) are commonly used for induction therapy in renal transplantation. This retrospective, single‐center, cohort study evaluated cumulative incidence of one‐yr biopsy‐proven acute rejection (BPAR) among 200 consecutive primary non‐sensitized kidney transplant recipients who received either alemtuzumab (n = 100) or rATG (n = 100) induction followed by rapid steroid taper, tacrolimus, and mycophenolate mofetil. Protocol biopsies, plasma and urine BK virus PCR, serum creatinine and iothalamate glomerular filtration rate (iGFR), were obtained at 1, 4, and 12 months from transplantation. The one‐yr BPAR rates were similar between the alemtuzumab and rATG groups; however, rejection Banff IA and higher was more common in the alemtuzumab arm (18% vs. 5%, p = 0.047). After adjusting for confounding variables, alemtuzumab was still associated with Banff IA and higher rejection (adjusted OR: 3.7, CI: 1.2–10.5, p = 0.02). Despite similar rates of BK viremia, more patients in the alemtuzumab arm developed BK nephropathy (16% vs. 3%, p = 0.046). One‐year iGFR (53.4 ± 20.2 vs. 71.9 ± 27.2 mL/min/1.73 m², p = 0.002) and three‐yr graft survival (89.5% vs. 95%, p = 0.05) were lower in the alemtuzumab group. In low immunological risk kidney transplant recipients on steroid‐free immunosuppression, alemtuzumab was associated with more severe rejection and BK nephropathy compared to rATG.     

The effect of rabbit antithymocyte globulin on human mesenchymal stem cells

Mesenchymal stem cells (MSCs) possess immunomodulatory properties which are of key interest for their application in autoimmunity and transplantation. In transplantation, administration of MSCs has shown promising results in preclinical models and has recently moved to clinical trials. Therefore, it is important to study the interactions between MSCs and immunosuppressive drugs currently used in transplantation. We aimed to analyze the effect of rabbit antithymocyte globulin (rATG) MSCs. MSCs were obtained from perirenal fat of kidney donors and exposed to ranging doses of rATG (Thymoglobulin^®, Genzyme; 0.5–100 μg/ml). Binding of rATG, effects on viability and susceptibility to be killed by cytotoxic lymphocytes as well as effects on their immunosuppressive potential of MSCs were tested. rATG binds dose‐dependently to MSCs. This binding was associated with slightly impaired viability after 48 and 72 h when compared with nonexposed MSCs. In contrast to nontreated MSCs, rATG preexposed MSCs were susceptible to be lysed by cytokine‐activated CD8⁺ cytotoxic cells and NKT cells. The capacity of MSCs to suppress the proliferation of anti‐CD3/CD28 activated CD4 and CD8 T cells were reduced by the presence of rATG in the culture. rATG reduces the viability and antiproliferative capacity of MSCs in a dose‐dependent manner and converts them into targets for CD8 T cells and NKT cell lysis.     

No clinical benefit of rapid versus gradual tapering of immunosuppression to treat sustained BK virus viremia after kidney transplantation: a single‐center experience

Immunosuppressive drug tapering is currently the recommended treatment of BK virus (BKV) viremia after kidney transplantation; however, its exact modalities remain unclear. We retrospectively compared two consecutive strategies in 111 patients with sustained viremia: a gradual monitoring/tapering group (GT, n = 57) before 2012 and a rapid monitoring/tapering group (RT, n = 54) after 2012. At viremia diagnosis, the dose of mycophenolic acid (MPA) and tacrolimus levels (T₀) were similar among patient groups. However, following onset, the dose of MPA at 1 month (P = 0.002) and 3 months (P = 0.005) and Tac T₀ at 1 month (P = 0.030) and 3 months (P = 0.006) were lower in the RT group. This rapid minimization shortened BKV viremia (P < 0.001) and resulted in a better protection of graft function in patients with confirmed BKV‐associated nephropathy (P = 0.033) without impacting 5‐year graft survival. Survival without rejection was similar (P = 0.571), but the RT group had increased the development of de novo donor‐specific antibodies (dnDSAs; P < 0.001). Multivariate Cox analysis identified basiliximab versus Thymoglobulin^® induction [hazard ratio (HR), 3.090; P = 0.001] and the RT strategy (HR, 6.021; P = 0.002) as independently associated with dnDSAs. Compared to a gradual tapering, rapid immunosuppression tapering to treat sustained BKV viremia does not improve medium‐term clinical outcome but increases the risk of developing dnDSAs.     

Lymphoproliferative disorder post renal transplantation: Recent experience at a single centre

Summary: Post-transplant lymphoproliferative disorder was diagnosed in six renal transplant recipients at the Royal Melbourne Hospital over a 5 year period to December 1994. This constituted a detection rate of 2.2%. All patients were treated with cyclosporine, azathioprine, prednisolone and orthoclone (OKT3). the median time of onset was 2 months (range 0.3 months-3 years) after transplant. Two patients who ultimately died presented with the diffuse form of the disease where immunoblasts massively infiltrated all organs. These tumours were monoclonal B cell lymphomas and Epstein-Barr virus (EBV) reactivation could be demonstrated. One patient developed a polyclonal B cell tumour with primary EBV infection and the remaining 3 patients tresented with T cell polyclonal proliferations and were EBV negative. No cytomegalovirus (CMV) infections, primary or reactionary were observed. Therapy in all cases consisted of reducing or ceasing immunosuppressive treatment and in three patients ganciclovir was used. Four polyclonal tumours responded to the treatment measures.     

Polyomavirus nephropathy after renal transplantation: a single centre experience

BACKGROUND: Polyomavirus associated nephropathy (PVN) in renal transplant recipients has been observed with increasing frequency recently and has emerged as a cause of allograft failure linked to highly potent new immunosuppressive regimens containing tacrolimus or mycophenolate mofetil (MMF). METHODS: Polyomavirus associated nephropathy was identified in nine out of 182 patients who received renal transplantation between October 1998 and July 2003. PVN was confirmed by allograft biopsy. The clinical records of these nine patients were reviewed, as were all of the allograft biopsies. Electron microscopy was performed in all nine cases. After the diagnosis of PVN, maintenance immunosuppression was reduced. The clinical course and outcome of the PVN patients were reviewed in relation to manipulation of immunosuppressive agents. RESULTS: There were nine cases of PVN in renal transplant recipients and the incidence of PVN was 4.9%. All patients with PVN were under triple immunosuppression comprising tacrolimus and MMF. The mean time to a diagnosis of PVN was 7.8 months after transplantation. Three of the nine patients received antirejection therapy prior to PVN. Seven out of nine PVN patients presenting acute allograft dysfunction were initially treated with high-dose intravenous steroid pulse or OKT3 before reduction of the immunosuppression. After reduction of the immunosuppression, seven patients stabilized their renal function. Two (22%) lost their grafts due to persistent PVN and chronic rejection. Two (22%) patients later developed acute rejection after reduction of the immunosuppression. CONCLUSION: PVN can cause allograft dysfunction and graft loss. Renal allograft recipients who are at risk of PVN should be routinely screened with urine cytology and quantitative measurements of viral load in the blood, particularly patients who had graft dysfunction. Early diagnosis and judicious alteration of immunosuppressive agents might permit a superior prognosis and reduce the graft loss from PVN in renal transplant recipients.     

The role of Thymoglobulin induction in kidney transplantation: an update

The rabbit antithymocyte globulin Thymoglobulin first became available over 25 yr ago and is the most widely used lymphocyte‐depleting preparation in solid organ transplantation. Thymoglobulin targets a wide range of T‐cell surface antigens as well as natural killer‐cell antigens, B‐cell antigens, plasma cell antigens, adhesion molecules and chemokine receptors, resulting in profound, long‐lasting T‐cell depletion. Randomized studies have established the anti‐rejection efficacy of Thymoglobulin in kidney transplantation. Experimental and clinical data suggest that Thymoglobulin administration may ameliorate ischemia reperfusion injury, thus reducing the incidence of delayed graft function (DGF). Studies have demonstrated the benefit of using Thymoglobulin to facilitate immunosuppression minimization, both for corticosteroid and calcineurin inhibitor (CNI) withdrawal or avoidance, with potential improvement in cardiovascular and renal outcomes. The optimal cumulative dose for Thymoglobulin induction is 6–7.5 mg/kg, with vigilant short‐ and long‐term monitoring of hematological status. Induction with Thymoglobulin is now indicated in immunologically high‐risk patients, in those at increased risk of DGF and to maintain efficacy in low‐risk transplant recipients receiving steroid or CNI minimization or avoidance regimens. We suggest that in future trials Thymoglobulin be tested with costimulation signal blockers and other immunosuppressants with the objective of establishing operational tolerance.     

Diarrhoea following renal transplantation

In this study, we retrospectively evaluated all attacks of diarrhoea in our renal transplant recipients that came to our medical attention between 1985 and 2000. Also, the clinical features of patients with diarrhoea were compared with the features of recipients without diarrhoea. We diagnosed 41 attacks of diarrhoea in 39 (12.6%) of 308 renal transplant recipients during this time period. An aetiology was detected in 33 (80.5%) of all diarrhoeal episodes and in seven (17.1%) of those the specific agent was diagnosed with the help of stool microscopy. The most frequent causes of diarrhoeal attacks were infectious agents (41.5%) and drugs (34%). Six (14.6%) episodes of diarrhoea were chronic and six were nosocomial. About two-thirds of diarrhoea developed within the late post-transplant period (>6 months). When recipients with diarrhoea were compared with those without diarrhoea, it was seen that diarrhoeal patients had significantly higher creatinine and significantly lower albumin levels when compared with the latter group (p < 0.05). Also, the frequency of antibiotic usage was significantly higher in diarrhoeal patients than in the control group (p < 0.05). Four (10.2%) patients with diarrhoea died despite institution of the appropriate therapy. Two of these deaths were primarily related to diarrhoea and the aetiological agent was Clostridium difficile in both these cases. During the 15-yr study period, 3.6% of all deaths and 5.1% of infection-related deaths in transplant recipients were secondary to diarrhoea. As a result, we observed that infections and drugs were the most frequent causes for diarrhoea in our series of renal transplant recipients. Also, diarrhoea was an important cause of mortality in this patient population.     

Prevention of acute rejection with antithymocyte globulin, avoiding corticosteroids, and delaying cyclosporin after renal transplantation.

BACKGROUND: Despite their well-known side-effects, corticosteroids (Cs) are currently used after kidney transplantation. Avoidance of Cs may improve patient quality of life and eventual long-term survival. We report on a regimen using antithymocyte globulin (ATG) and mycophenolate mofetil (MMF) for induction, and cyclosporin (CsA) plus MMF for maintenance treatment of recipients of primary kidney transplantation. METHODS: We studied 11 consecutive, non-sensitized renal transplant patients (nine cadaver and two living donors). Initial immunosuppression consisted of ATG (1.5 mg/kg/day, i.v.) given for 10 days and MMF (1.0 g/b.i.d.). CsA (8 mg/kg, in two divided doses) was started on post-operative day 11. Cs were only allowed in the case of MMF discontinuation, for the treatment of acute rejection, and in the event of recurrence of the primary glomerulonephritis. RESULTS: All patients completed the entire 10-day ATG course. Main side-effects included fever (>38 degrees C) and serum sickness, observed in 73 and 27% of the patients respectively. The incidence of acute rejection was 27% (three of 11 patients). In two patients with acute rejection, serum sickness was concomitantly diagnosed and renal histology was partially compatible with immune-complex disease. The remaining patient had two episodes of low-grade rejection. All rejection episodes were rapidly reversed. Two patients (18%) were treated with ganciclovir for cytomegalovirus (CMV) infection. Two patients (18%) are currently receiving Cs for recurrence of the native glomerulonephritis and two rejection episodes respectively. All patients are currently alive with functioning kidneys (average follow-up of 8.4 months; average creatinine level of 128 micromol/l). CONCLUSION: This pilot study suggests that ATG induction in combination with MMF and delayed introduction of CsA, in the absence of Cs, is not well tolerated in recipients of kidney transplants. An earlier introduction of calcineurin inhibitors and/or a shorter course of ATG may reduce the incidence of fever and serum sickness secondary to ATG.     

Latest insights on ABO-incompatible living-donor renal transplantation

This review summarizes the latest insights on ABO-incompatible living-donor renal transplantation. Desensitization protocols and clinical outcomes were investigated, and a comparison was made with kidney-paired donation, which is not permitted in Japan for ethical reasons. Although renal transplantation is greatly beneficial for most patients with end-stage kidney disease, many of these patients must remain on dialysis therapy for extended periods due to the scarcity of organs from deceased donors. ABO blood type incompatibility was once believed to be a contraindication to renal transplantation due to the increased risk for antibody-mediated rejection and early graft loss attributable to isoagglutinins. Recently, pretransplant desensitization strategies, such as removal of isoagglutinins and antibody-producing cells, have achieved successful outcomes, although it remains unclear whether graft survival and patient morbidity are equivalent to those for ABO-compatible renal transplantation. The present review suggested that ABO-incompatible living-donor renal transplantation might be a favorable radical renal replacement therapy for patients with end-stage kidney disease.     

Prospective study of polyomavirus BK replication and nephropathy in renal transplant recipients in China: a single‐center analysis of incidence,reduction in immunosuppression and clinical course

Huang G, Chen L‐Z, Qiu J, Wang C‐X, Fei J‐G, Deng S‐X, Li J, Chen G‐D, Zhang L, Fu Q, Zeng W‐T, Zhao D‐Q. Prospective study of polyomavirus BK replication and nephropathy in renal transplant recipients in China: a single‐center analysis of incidence, reduction in immunosuppression and clinical course.
Clin Transplant 2009 DOI: 10.1111/j.1399‐0012.2009.01141.x
© 2009 John Wiley & Sons A/S. Abstract: Background: BK virus (BKV)‐associated nephropathy (BKVAN) in renal transplant recipients is an important cause of renal transplant dysfunction. Our aim was to determine the kinetics of BKV load within one yr after kidney transplantation under the impact of intensive monitoring and reduction in maintenance immunosuppression, the incidence of BKVAN, and the outcome of BKVAN treatment. Methods: Urine and peripheral blood (PB) were taken from 90 renal transplant recipients for BKV cytological testing and real‐time PCR for BKV DNA at one, three, six, nine, and 12 months after transplantation and treatment. Graft biopsies and urinary sediments of recipients with BKVAN were taken to monitor viral particles by conventional transmission electron microscopy (TEM). Results: By one post‐transplant year, urinary decoy cells (median, 8/10 HPF), BKV viruria (median, 2.60 × 10⁵ copies/mL), viremia (median, 9.65 × 10³ copies/mL ) , and BKVAN occurred in 42.2%, 45.6%, 22.2%, and 5.6% of patients, respectively. The incidence of BK infection was lower in patients who received cyclosporine A (CsA) (28.9%) compared to tacrolimus (FK506) (57.7%) (p = 0.007). An increased hazard of BK infection was associated with the use of FK506 (HR 2.6, p = 0.009) relative to CsA. After reduction in immunosuppression, viremia resolved in 95%, without increased acute rejection, allograft dysfunction, or graft loss. BKVAN was diagnosed in five patients (5.6%). The treatment of immunosuppression reduction was effective (i.e., decreased the viral load and number of decoy cells, and improved graft function) in our five patients with BKVAN. Quantitative count of decoy cells (e.g., >10 per 10 HPF) as a marker of viremia and BKVAN had increased positive predictive values of 85.7% and 57.1%, respectively. Conclusions: Choice of FK506 as immunosuppressive agent is an independent risk factor affecting BKV infection. Monitoring and pre‐emptive of immunosuppression reduction were associated with resolution of viremia and showed effective in BKVAN recipients at the early stage without acute rejection or graft loss. Quantitative count of urine cytology is a very convenient, useful, and sensitive method for evaluating BKV infection in renal transplant recipients.     

A pitfall in screening with decoy cells after simultaneous pancreas kidney transplantation

In this report, we describe a bladder-drained simultaneous pancreas-kidney transplant (SPKT) recipient with a polyoma virus-associated nephropathy (PVAN) in whom the urine cytology failed to detect decoy cells despite repeated attempts. Several tests were performed to confirm our hypothesis that pancreatic enzymes can degrade decoy cells and granulocytes. This case illustrates an important pitfall in the urinary screening for PVAN with cytology and for urinary tract infections with urine sediment in bladder-drained SPKT recipients.     

肾移植受者预防性应用兔抗人胸腺细胞免疫球蛋白的有效性和安全性

目的 探讨肾移植受者预防性应用兔抗人胸腺细胞免疫球蛋白(ATG-R)的有效性和安全性.方法 选择2003年5月至2006年12月期间的肾移植受者655例,分为试验组(84例)和对照组(571例).两组受者在年龄、性别、群体反应抗体(PRA)、HLA配型、常规免疫抑制剂的应用等方面比较,差异无统计学意义.对试验组受者采取术前1次较大剂量(1.5 mg/kg)和术后短时间小剂量(0.5～1 mg/kg)预防性应用ATG-R;对照组受者仅采用常规免疫抑制方案.分析和比较两组受者术后移植物功能延迟恢复(DGF)发生率、术后6个月内急性排斥反应(AR)发生率、术后6个月内感染发生率及人/肾1年存活率等指标.结果 试验组和对照组DGF发生率分别为2.38%和8.40%,试验组明显低于对照组,差异有统计学意义(P＜0.01);术后6个月内AR发生率分别为4.76%和11.03%,试验组低于对照组,差异有统计学意义(P＜0.05);试验组和对照组术后6个月内感染发生率分别为10.71%和9.81%,两组比较,差异无统计学意义(P＞0.05).两组的人/肾1年存活率比较,差异也无统计学意义(P＞0.05).结论 肾移植受者预防性应用ATG-R能够明显降低DGF和AR发生率,且不增加感染发生率,是一种有效和安全的免疫诱导措施.     

肾移植术后BK病毒感染的危险因素分析

目的 分析肾移植术后BK病毒(BKV)感染发生的危险因素.方法 应用荧光实时定量PCR技术检测129例肾移植患者血液中BKV并行尿液细胞学检查,记录BKV-DNA阳性及阴性组患者性别、年龄、供肾冷缺血时间,术前血液透析时间、急性排斥反应、是否发生移植肾功能延迟恢复、免疫抑制剂方案、合并其他病毒感染等指标.应用二项多元逻辑回归法分析肾移植术后BKV感染发生的危险因素.结果 129例患者血中BKV-DNA阳性20例(15.5%).阴性109例(84.5%);BKV-DNA阳性患者尿细胞学检测Decoy细胞阳性15例,尿Decoy细胞阳性率与血BKV-DNA阳性率之间有明显的相关性(r=0.428,P<0.01).回归分析结果 显示:供肾冷却血时间(χ~2=9.243,95%CI:1.099～1.545,P<0.05)、患者术前透析时间(χ~2=7.599,95%CI:1.038～1.243,P<0.05)、是否为亲体供肾(χ~2=4.150,95%CI:0.012～0.070,P<0.05)为BKV感染的危险因素.结论 荧光实时定量PCR及尿细胞学检查可以作为肾移植术后BKV感染的筛查指标;供肾冷缺血时间长、术前血液透析时间长、尸体供肾均可增加患者术后BKV感染的风险.     

Analysis of a single-center experience with mycophenolate mofetil based immunosuppression in renal transplantation

Purpose. Acute rejection continues to be a major clinical issue in renal transplantation. Three large multicenter trials have demonstrated a 50% decline in biopsy‐proven rejection when mycophenolate mofetil (MMF) was given to renal transplant recipients with corticosteroids and cyclosporine. The purpose of this study was to compare the 6‐month outcome of renal transplant recipients using MMF and non‐MMF based immunosuppression protocols over a 4‐year period at a single center.
Methods. This retrospective study analyzed three patient groups defined by their immunosuppression protocol. The first group included patients who received a quadruple immunosuppression regimen of antilymphocyte induction (ATG), cyclosporine (CYA), azathioprine (AZA), and corticosteroids (CCS), and were transplanted between October 1993 and May 1995 (AZA group). The second group included patients who received a triple immunosuppression regimen of CYA, MMF, and CCS, and were transplanted between June 1995 and May 1996 (MMF group). The third group included patients who were transplanted between January 1997 and December 1997, and received an immunosuppression regimen of CYA and MMF with a reduced CCS dosing schema (reduced steroid group (RST)). Data were collected from a retrospective review of inpatient and outpatient clinical records.
Results. A total of 325 patients were included in the study (106 AZA, 106 MMF, 113 RST). The demographic characteristics of the three groups were similar; however, the mean donor age for the AZA group was 40±15.1 years versus 33±14.1 years and 34±13.1 years for the MMF and RST groups, respectively (p<0.043). The incidence of acute, biopsy‐proven rejection at 6 months was significantly less in the MMF group when compared with the AZA group [16 (15.1%) versus 35 (33%) patients, p=0.002]. However, the incidence of acute, biopsy‐proven rejection in the RST group (35 patients, 31%) was similar to that of the AZA group. Kaplan–Meier estimates for the cumulative incidence of acute rejection demonstrated a significant difference between the MMF group and the other two groups (p=0.0059). The AZA group had more severe rejection as demonstrated by the more frequent use of antilymphocyte therapy for rejection treatment (68.4% episodes) compared with the MMF (38.9%) and RST (47.6%) groups. After 6 months of follow‐up, 11 patients had lost their grafts (8, AZA; 1, MMF; 2, RST). One patient died in each of the AZA and RST groups due to hemorrhage and a pulmonary embolus, respectively. Four AZA patients were diagnosed with a malignancy (three post‐transplant lymphoproliferative disorder, one squamous skin cell carcinoma) compared with 2 MMF patients (prostate cancer, basal skin cell carcinoma) and no RST patients. Herpes zoster was the only infection that occurred more frequently in the MMF group (p=0.03). No other differences in infection rates were noted among the three groups. The initial length of hospital stay declined significantly over the 4‐year study period [11±4.3 d (AZA), 7.0±4.0 d (MMF), 6.2±3.3 d (RST), p<0.001]. Total number of hospital days for the first 6 months also followed a similar declining pattern. Despite using intravenous cyclosporine immediately post‐transplant in the MMF and RST groups, the incidence of delayed graft function was similar among the three groups. Average serum creatinine at 1 month was significantly lower in the MMF group (p=0.008), but no difference was noted at 3 and 6 months when compared with the AZA and RST groups.
Conclusion. This retrospective analysis indicates that MMF is an effective immunosuppressant. Decreased length of stay and less steroid resistant rejections with MMF is favorable for decreased hospital costs. However, the rebound in rejection rate with the RST group suggests that further study is needed to define the optimal use of this agent in combination with others to maximize effectiveness and minimize negative side effects.     

Predictors of new onset diabetes after renal transplantation

The development of new onset diabetes after transplantation (NODAT) is associated with increased cardiovascular morbidity and mortality. This study aimed at identifying risk factors for the development of NODAT. We performed a retrospective review of 787 renal transplants performed between 1994 and 2004 at a single centre. NODAT was diagnosed in patients who had two random plasma glucose concentrations >11.1 mmol/L after the first month post-transplant or patients who required treatment for hyperglycaemia within the first month and continued treatment thereafter. The incidence of NODAT was 7.7%. The incidence of NODAT requiring either insulin or oral hypoglycaemic agents was 4.5%. Risk factors for the development of NODAT were older age (HR 1.04, 95% CI: 1.01-1.07, p < 0.01), heavier weight at time of transplantation (HR 1.04, 95% CI: 1.02-1.07, p < 0.01), higher mean pre-transplant random plasma glucose concentrations (HR 1.54, 95% CI: 1.14-2.08, p < 0.01), higher plasma glucose within the first seven d post-transplant (HR 1.27, 95% CI: 1.09-1.47, p < 0.01) and use of tacrolimus (HR 3.70, 95% CI: 1.61-8.46, p < 0.01). Ten yr actuarial patient survival was 67.1% in patients with NODAT compared with 81.9% for those without diabetes and 65.3% in patients known to have diabetes pre-transplant. There was no difference in graft survival. We have identified a high-risk group in which attempts should be made to reduce the incidence of NODAT by tailoring immunosuppression, lifestyle modification and selecting non-diabetogenic medications. Improvements in management of patients at higher risk of NODAT may help reduce the incidence of deaths with a functioning graft.     

The renal benefit of mycophenolate mofetil after liver transplantation

Haywood S, Abecassis M, Levitsky J. The renal benefit of mycophenolate mofetil after liver transplantation.
Clin Transplant 2011: 25: E88–E95. © 2010 John Wiley & Sons A/S. Abstract: Background: The risk and benefit of adding mycophenolate mofetil (MMF) to a standard immunosuppressive regimen at the time of liver transplantation (LT) is not well described. Methods: We performed a retrospective case–control analysis comparing one‐yr outcomes of all LT recipients at our institution treated with post‐operative tacrolimus (TAC), MMF, and steroids vs. TAC and steroids. Results: A total of 101 LT recipients (50:51 case:control) were analyzed. Despite more renal dysfunction at LT, the MMF + TAC group had similar serum creatinine (Cr) and glomerular filtration rate (GFR) as the TAC group one‐yr post‐LT. In this time period, Cr decreased (1.57–1.22 mg/dL, p = 0.04) and GFR increased (57.5–65.1 mL/min per 1.73 m², p = 0.05) in the MMF + TAC group, while Cr increased (1.11–1.35, p < 0.01) and GFR declined (73.5–60.1, p < 0.001) in the TAC group. These findings occurred without a difference in absolute rejection episodes, hospitalizations, infections, deaths, or time to above events (p > 0.05). Subgroup analysis of patients stratified by pre‐transplant renal dysfunction (Cr ≥ 1.2 mg/dL) supported the previous. MMF was reasonably well tolerated with a low rate of discontinuation. Conclusions: The use of adjunctive MMF immediately after LT may protect against calcineurin inhibitor nephrotoxicity, potentially without the need for dose reduction or increased risk of adverse events.     

Adverse impact of pretransplant polyoma virus infection on renal allograft function

Background: BK polyoma virus (BKV) has emerged as an important cause of acute and chronic allograft injury in renal transplant recipients. Reactivation of latent infection requires reduction in cell‐mediated immunity. We hypothesized that BKV could get reactivated in the urinary tract of patients with end‐stage renal disease (ESRD) and impact the allograft function after these individuals undergo transplantation. Methods: We prospectively examined the urine specimens of 68 ESRD patients and their donors for BKV inclusion containing decoy cells with Papanicoulau staining and immunohistochemistry. Polymerase chain reaction was carried out to confirm the presence of viral DNA. Urine examination was repeated 3–9 months after transplantation and during episodes of graft dysfunction. All graft dysfunction episodes were investigated by biopsy. BKV‐associated nephropathy was confirmed by immunoperoxidase staining. Graft loss and doubling of serum creatinine were the study end‐points. Results: Decoy cells were detected in 22 ESRD patients and four donors (P < 0.0001). All 22 continued decoy cell excretion after transplantation and two fresh excreters were noted. Patients exhibiting decoy cells had more frequent graft dysfunction episodes (67% vs 30%, P = 0.003) and higher serum creatinine value (P < 0.001). About 33% patients achieved the combined end‐points in the BK viruria group, compared with 11% in the non‐decoy cell excreters (P = 0.03). Histologically proved BKV nephropathy was noted in 7% cases; all decoy cell excreters. Conclusion: We conclude that reactivation of latent BKV infection can occur in ESRD and confers an increased risk of graft dysfunction after transplantation. The mechanism of graft dysfunction in decoy cell excreters who do not develop overt nephropathy needs more studies.     

A prospective economic evaluation of basiliximab (Simulect) therapy following renal transplantation

BACKGROUND: Immunoprophylaxis with basiliximab (Simulect), an anti-interleukin-2-receptor (anti-IL-2R; CD25) chimeric monoclonal antibody, has been demonstrated to significantly reduce the incidence of acute cellular rejection in adult renal allograft recipients (32% vs. placebo, p < 0.01). METHODS: An economic evaluation was conducted as part of a U.S. multi-center, randomized, double-blind, placebo-controlled clinical trial comparing basiliximab plus dual immunosuppressive therapy (cyclosporine modified [Neoral] and corticosteroids) to dual therapy alone. Healthcare resources utilized by the 346 subjects in the 'intent-to-treat' population were prospectively collected over the 1-yr study period. Direct medical costs were determined for all hospitalizations, outpatient provider visits, procedures (excluding the initial transplant procedure), laboratory and diagnostic tests, and immunosuppressants, including basiliximab when administered. RESULTS: Total first-year medical costs were lower for the basiliximab group than for the placebo group ($28 927 vs. $32 300, difference = $3373). although this difference was not statistically significant. First-year hospital costs for treating acute rejection were also lower for the basiliximab group ($9328 vs. $10761, difference = $1433); however, this difference did not achieve statistical significance. Importantly, the efficacy analysis demonstrated a significant reduction in the incidence of acute rejection (38 vs. 55%, p < 0.01) in the basiliximab arm, and this was accomplished without increasing the overall cost of care. Fewer basiliximab-treated patients (8 vs. 15%,, p = 0.03) were hospitalized. This observation suggested less serious illness and reduced treatment costs among basiliximab-treated patients, because the overall incidence of infection was similar between the groups. The adverse event profile of patients receiving basiliximab was clinically and economically indistinguishable from that of those treated with placebo. CONCLUSION: Induction immunosuppression with basiliximab, combined with cyclosporine modified and corticosteroids, was therapeutically beneficial and contained medical costs during the initial post-transplant year.     

Efficacy of conventional immunosuppressive therapy in related and unrelated living renal transplantation

BACKGROUND: The application of antibody induction therapy in adult living-related kidney transplantation remains under discussion. The purpose of this study was to compare the outcome of living-related (LRT) and unrelated renal transplant recipients (LURT) using standardized immunosuppressive protocols. From October 2000 to October 2004, 72 adult LRT (TX) were performed at our institution. Thirty-nine LRT (group A) and 33 LURT (group B) recipients received a standardized immunosuppressive therapy consisting of tacrolimus (Tac), steroids and mycophenolate mofetil (MMF) without antibody induction therapy. This prolective analysis included immediate graft function, rejection rate and loss of the transplanted organ. The incidence of post-operative good graft function (>90%) was similar for both groups, as well as the rejection rate showed 57.8% for patients of group A and 58.8% for patients of group B (p < 0.5). However, the number of rejections (>1 rejection) was significantly higher in group B (11.8%) compared to patients in group A (4.4%). No difference concerning loss of transplanted kidney was observed for both groups. Conventional Tac, MMF and steroid-based immunosuppression therapy is equivalent in efficacy of therapy in living-related and unrelated renal transplants. In our opinion, induction therapy in patients without immunologic risk factors has no favourable effect.